Pancreatic ductal adenocarcinomas (PDA) are highly lethal malignancies accounting for over 160,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how PDAs progress in order to design more rational, targeted therapy. We are studying the molecular pathways that lead to tumor progression in PDA. Our focus is the HMGA1 oncogene, which encodes the HMGA1a and HMGA1b protein isoforms. These chromatin binding proteins function in regulating gene expression. Our preliminary studies show that HMGA1 is overexpressed in human PDA, with high levels in invasive, metastatic tumors, but no expression in normal pancreas or early precursor lesions. We also discovered that HMGA1a cooperates with the activated RAS oncogene and confers a transformed phenotype in cultured human pancreatic cells derived from normal pancreatic tissue. Specifically, cells engineered to overexpress activated RAS and HMGA1a form foci in soft agar and tumors in nude mice. Inhibiting HMGA1 function in metastatic, human PDA cells blocks the transformed phenotype in vitro and metastases in an orthotopic mouse model for PDA in vivo. These findings suggest that HMGA1 promotes tumor progression in PDA. We also showed that HMGA1 up-regulates the cyclo-oxygenase-2 (COX-2) gene in some tumors. The COX-2 gene is highly expressed in human cancers, including PDAs, and is thought to contribute to tumorigenesis. Our preliminary results show high levels of COX-2 protein in PDAs with high expression of HMGA1. In a preclinical pilot study, we also found that COX-2 inhibitors block tumorigenesis in nude mice with human PDA xenografts. Based on these findings, we hypothesize that the HMGA1-COX-2 pathway promotes tumor progression in PDA. Using our unique experimental reagents, we now propose to test our hypothesis with the following Specific Aims: 1.) Determine if HMGA1a and COX-2 protein levels correlate with more advanced disease in PDA, 2.) Determine if COX-2 is a downstream target of HMGA1 in PDA, and, 3.) Determine if targeting the HMGA1-COX-2 pathway is effective in blocking PDA tumor progression in our experimental models. Results from these studies will enhance our understanding of the molecular pathways that lead to pancreatic cancer progression and should enable us to develop better therapies. PUBLIC HEALTH RELEVANCE: There is a dire need for research to identify rational therapies for pancreatic cancer because virtually all patients with this cancer die from disease progression. This year alone, over 30,000 people in the U.S. will succumb to pancreatic cancer with over 160,000 deaths worldwide. In this grant, we propose studies to identify cellular pathways important in the development of pancreatic cancer with emphasis on those that could be targeted in therapy.